Malarial disease in children - Extenstion to ophthalmological studies in Blantyre 2007-8. (360G-Wellcome-074125_Z_04_A)

In malarious areas most P falciparum infections cause either few symptoms or none, but an important minority progress to severe disease. In three linked studies we propose to investigate the acquisition of specific humoral immunity in infancy and mechanisms of severe disease in Malawian children infected with P falciparum. In Study I we will follow cohorts of HIV-infected and HIV-uninfected infants, identifying and characterising malaria infections, illnesses and responses to treatment. We will measure functional humoral responses directed against three separate targets - variant specific antigens on the infected red cell surface (mediating cytoadherence); merozoite surface protein-1 (mediating invasion of red cells by merozoites); and a putative malaria toxin (mediating fever). In each case we will compare responses between HIV-infected and HIV-uninfected infants, and analyse malarial infections and illnesses according to antecedent serological status. This study will increase our understanding of specific mechanisms of protection against malaria, and of the impact of HIV on these mechanisms. Study II is an investigation of pathogenesis in severe malaria. We postulate that platelets mediate the adhesion of parasitised red blood cells (pRBC) to each other and to endothelial cells and monocytes, thus contributing to pathology. We will study the in vitro adherence between pRBC (from both mild and severe malaria cases) and (a) other pRBCs, (b) cultured human cerebral endothelial cells and (c) host monocytes, analysing the ligands on both pRBC and host cells that mediate these adhesions. In Study III we will investigate retinopathy and intracranial pressure (ICP) in patients with malarial coma. We will use ultrasonography of the optic nerve - a non-invasive, quick and safe measure of intracranial pressure - to study levels and changes in IPC in relation to clinical characteristics and prognosis, and in relation to the unique retinopathy of malaria. We will test the hypothesis that retinal whitening is associated with increased ICP and that a common mechanism in brain and retina may underlie both phenomena.